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Antipsychotics

Open AccessPublished:April 08, 2011DOI:https://doi.org/10.1016/j.jpainsymman.2011.03.002
      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativebooks.com. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations/Key

      5HT2A, 5HT2C, 5HT3
      5 Hydroxytryptamine-2A, -2C and -3 receptors
      α1, α2
      Alpha-1 and -2 receptors
      AChM
      Anticholinergic (muscaric) receptor
      CYP
      Cytochrome P450
      D2
      Dopamine-2 receptor
      H1
      Histamine-1 receptor
      PO
      Per os, by mouth
      RCT
      Randomized controlled trial
      SC
      Subcutaneous
      SSRI
      Selective serotonin reuptake inhibitor
      Indications: Licensed indications vary between products; consult the manufacturer’s Product Insert for details. Uses include acute psychotic symptoms, mania and bipolar disorders, schizophrenia, agitation, delirium, nausea and vomiting, intractable hiccup, treatment-resistant depression.
      • Mahmoud R.A.
      • Pandina G.J.
      • Turkoz I.
      • et al.
      Risperidone for treatment-refractory major depressive disorder: a randomized trial.

      Neurophysiology of Dopamine

      Dopamine has a central role in arousal, motivation, attention, the extrapyramidal motor system and other pathways (Table 1). Although the exact etiology is uncertain, dopamine dysregulation plays a role in a number of symptoms, e.g., nausea, hallucinations, and dopamine antagonist drugs such as antipsychotics can help palliate these. An appreciation of the neurophysiology of dopamine facilitates a fuller understanding of the numerous therapeutic uses and undesirable effects of antipsychotics.
      Table 1Dopaminergic Pathways
      PathwayFunctionSymptoms of Dysregulation
      Mesolimbic

      Midbrain reticular formation → limbic cortex
      Pleasure, motivation and reward
      Both the mesolimbic and thalamic dopamine pathways affect thalamic sensory gating. Mesolimbic dysregulation is best characterized in the formation of “positive” psychotic symptoms (see text).
      ↑Dopamine: “positive” symptoms of psychosis (delusions, hallucinations)
      Mesocortical system

      Midbrain reticular formation → prefrontal cortex
      Affect, executive function, concentration↓Dopamine: depression; “negative” symptoms of psychosis (apathy, anhedonia and cognitive blunting)
      Nigrostriatal system

      Substantia nigra → corpus striatum
      Extrapyramidal motor system↓Dopamine: Parkinson’s disease, drug-induced parkinsonism, akathisia, dystonia, restless legs

      ↑Dopamine: dyskinesia
      Tuberoinfundibular systemDopaminergic inhibition of prolactin secretion↓Dopamine: hyperprolactinemia
      Thalamic dopamine pathway
      Both the mesolimbic and thalamic dopamine pathways affect thalamic sensory gating. Mesolimbic dysregulation is best characterized in the formation of “positive” psychotic symptoms (see text).


      Multiple origins → thalamus
      Sleep and arousal through sensory gating
      Area postremaEmetogenesis↑Dopamine: nausea and vomiting
      a Both the mesolimbic and thalamic dopamine pathways affect thalamic sensory gating. Mesolimbic dysregulation is best characterized in the formation of “positive” psychotic symptoms (see text).
      Psychotic symptoms arise from opposing dopamine imbalances:
      • “positive” symptoms (delusions and hallucinations) result from dopamine excess in the mesolimbic system
      • “negative” symptoms (apathy, anhedonia and cognitive blunting) result from dopamine deficit in the mesocortical system.
      Arousal, motivation and attention are regulated by a two-way loop between the prefrontal/limbic cortex and the thalamus. The prefrontal/limbic cortex identifies situations requiring attention and the thalamus is directed to allow relevant information to pass through to the cerebral cortex while filtering out the rest. This thalamic sensory filter is formed by GABAergic neurons, which are switched off by dopamine to allow salient information through. In psychosis, dopamine overactivity leads to excessive information throughput, resulting in hallucinations and delusions (the “salience hypothesis”). D2 antagonist antipsychotics help to correct this overactivity, and improve these symptoms.
      • Stahl S.M.
      Antipsychotic agents.
      • Boutrel B.
      • Koob G.F.
      What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications.
      • Alves Fda S.
      • Figee M.
      • Vamelsvoort T.
      • Veltman D.
      • de Haan L.
      The revised dopamine hypothesis of schizophrenia: evidence from pharmacological MRI studies with atypical antipsychotic medication.
      • Stahl S.M.
      Psychosis and schizophrenia.
      Conversely, D2 antagonists augment dopaminergic underactivity in the mesocortical system, leading to, or exacerbating, “negative” symptoms.
      • Stahl S.M.
      Antipsychotic agents.
      • Alves Fda S.
      • Figee M.
      • Vamelsvoort T.
      • Veltman D.
      • de Haan L.
      The revised dopamine hypothesis of schizophrenia: evidence from pharmacological MRI studies with atypical antipsychotic medication.
      • Stahl S.M.
      Psychosis and schizophrenia.
      D2 antagonism can also disrupt other pathways unaffected by psychosis:
      • nigrostriatal system, part of the extrapyramidal motor system:
        • D2 antagonists initially cause underactivity, similar to Parkinson’s disease → acute extrapyramidal symptoms
        • subsequent adaptation to D2 antagonism leads to D2 receptor upregulation → tardive dyskinesia
      • tuberoinfundibular system; D2 antagonists cause hyperprolactinemia → sexual dysfunction.
      The newer “atypical” antipsychotics have been developed in an attempt to overcome some of the above limitations of “typical” D2 antagonists.

      Pharmacology

      Conventionally, antipsychotics are divided into two classes:
      • typical:
        • phenothiazines: chlorpromazine, levomepromazine (not USA), perphenazine, prochlorperazine, promazine, trifluoperazine
        • butyrophenones: haloperidol
      • atypical: aripiprazole, clozapine, olanzapine, quetiapine, risperidone.
      However, there is much variation within, and overlap between, these classes. Although all antipsychotics are characterized by D2 antagonism, differences in receptor profile result in clinical differences between them (Table 2).
      • Jindal R.D.
      • Keshavan M.S.
      Classifying antipsychotic agents: need for new terminology.
      Antipsychotics are variably associated with antagonistic effects at the following receptors:
      • muscarinic, causing dry mouth, constipation, etc.
      • adrenergic, causing postural hypotension
      • histaminic, causing drowsiness.
      Table 2Receptor Affinities for Selected Antipsychotics
      • Jindal R.D.
      • Keshavan M.S.
      Classifying antipsychotic agents: need for new terminology.
      • Lal S.
      • Nair N.P.
      • Cecyre D.
      • Quirion R.
      Levomepromazine receptor binding profile in human brain–implications for treatment-resistant schizophrenia.

      National Institute of Mental Health (NIMH). NIMH’s psychoactive drug screening program. 2006. University of North Carolina. Available from http://pdsp.med.unc.edu/indexR.html.

      • Shiloh R.
      • Stryjer R.
      • Weizman A.
      • Nutt D.
      • et al.
      Antipsychotic drugs.
      D25HT2A5HT2C5HT3H1α1α2AChM
      Aripiprazole+++PA++++++-++++++++-
      Chlorpromazine++++++++-+++++++++
      Clozapine+++++++++++++++
      Haloperidol++++---++--
      Levomepromazine (not USA)++++++++++++++
      Perphenazine+++++++++++++-
      Prochlorperazine++++++-++++-+
      Olanzapine+++++++++++++
      Quetiapine+++-+++++-
      Risperidone++++++++-++++++-
      Affinity: +++ high, ++ moderate, + low, (+) borderline, - negligible or none; blank=no data. PA=partial agonist.
      In contrast, the D2-specific action of haloperidol avoids such problems, but increases the risk of extrapyramidal effects.
      Atypical antipsychotics carry a lower risk of extrapyramidal effects and improved efficacy for negative symptoms. This relates to:
      • Stahl S.M.
      Antipsychotic agents.
      • Kapur S.
      • Mamo D.
      Half a century of antipsychotics and still a central role for dopamine D2 receptors.
      • Lieberman J.A.
      Dopamine partial agonists: a new class of antipsychotic.
      • 5HT2 receptor antagonism
      • D2 partial agonism
      • lower affinity and shorter duration D2 antagonism.
      5HT2 receptors inhibit the nigrostriatal and mesocortical systems. Thus, 5HT2 antagonist antipsychotics increase activity in these pathways, countering the extrapyramidal impact of D2 antagonism and improving “negative” symptoms.
      • Meltzer H.Y.
      What’s atypical about atypical antipsychotic drugs?.
      “Negative” symptoms overlap with depressive symptoms and can respond to antidepressants.
      • Rummel C.
      • Kissling W.
      • Leucht S.
      Antidepressants for the negative symptoms of schizophrenia.
      Conversely some 5HT2 antagonist antipsychotics are beneficial in refractory depression (e.g., olanzapine).

      Millan MJ, Gobert A, Rivet JM, A, et al. Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram. Eur J Neurosci 2000;12:1079–1095.

      • Shelton R.C.
      • Osuntokun O.
      • Heinloth A.N.
      • Corya S.A.
      Therapeutic options for treatment-resistant depression.
      It is noteworthy that increased prefrontal dopamine release through 5HT2 antagonism is also an important action of some antidepressants, e.g., mirtazapine.
      An antipsychotic that acts as a D2 partial agonist will function as a D2 antagonist in the presence of excessive dopamine (e.g., as in the mesolimbic system in psychosis), because partial activation of the D2 receptor will reduce overall transmission. However, when there is dopamine depletion, the partial D2 receptor activation is sufficient to increase overall transmission, and it functions as a D2 agonist, e.g., in the nigrostriatal and mesocortical systems. In consequence, a D2 partial agonist antipsychotic can potentially improve both “positive” and “negative” symptoms and limit undesirable extrapyramidal effects.
      However, the extent to which atypical antipsychotics succeed in practice in reducing extrapyramidal effects and negative symptoms is unclear. The relatively lower doses of atypicals used in RCTs with typicals may partly explain some of the observed differences. Further, the properties purported to account for such differences also are shared by some typical antipsychotics, e.g., 5HT2 antagonism. On the other hand, the higher incidence of other undesirable effects (particularly metabolic) with atypicals limits improvement in overall tolerability.
      Direct comparisons suggest that acute extrapyramidal effects would be avoided in one patient for every 3–6 patients treated with an atypical rather than a typical antipsychotic.
      • Wahlbeck K.
      • Cheine M.
      • Essali M.A.
      Clozapine versus typical neuroleptic medication for schizophrenia.
      • Hunter R.H.
      • Joy C.B.
      • Kennedy E.
      • Gilbody S.M.
      • Song F.
      Risperidone versus typical antipsychotic medication for schizophrenia.
      However, the difference is greatest relative to haloperidol. Further, in an RCT, although extrapyramidal effects accounted for more discontinuations of perphenazine compared with several atypicals (8% vs. 2–4%), overall discontinuation rates for undesirable effects or lack of efficacy were comparable.
      • Lieberman J.A.
      • Stroup T.S.
      • McEvoy J.P.
      • et al.
      Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
      All treatment groups experienced some degree of involuntary movement (13–17%), akathisia (5–9%) or extrapyramidal signs (4–8%). Most studies are too short to evaluate the risk of tardive dyskinesia. Available data suggest a five times lower risk with atypicals compared with haloperidol in the first year of use, although haloperidol doses were relatively higher.
      • Correll C.U.
      • Leucht S.
      • Kane J.M.
      Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies.
      Among atypicals, risperidone carries the highest risk of extrapyramidal effects, and clozapine and quetiapine the lowest.
      • Haddad P.M.
      • Sharma S.G.
      Adverse effects of atypical antipsychotics: differential risk and clinical implications.
      Acquisition costs for atypicals are higher than for typicals. Suggested reductions in costs from the long-term use of atypicals may be less relevant in palliative care if drugs are used at lower doses and for shorter periods.
      • Davies A.
      • Langley P.C.
      • Keks N.A.
      • et al.
      Risperidone versus haloperidol: II. cost-effectiveness.
      Pharmacokinetic details of selected antipsychotics are summarized in Table 3.
      Table 3Pharmacokinetic Details for Selected Antipsychotics
      • Eiermann B.
      • Engel G.
      • Johansson I.
      • Zanger U.M.
      • Bertilsson L.
      The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine.
      • Finn A.
      • Collins J.
      • Voyksner R.
      • Lindley C.
      Bioavailability and metabolism of prochlorperazine administered via the buccal and oral delivery route.
      Oral Bioavailability (%)Time to Peak Plasma ConcentrationHalf-Life (h)Metabolism

      (Predominant P450 Isoenzyme)
      Chlorpromazine10–252–4 h (PO)30CYP2D6
      Clozapine50–602 h12CYP1A2, CYP3A4
      Haloperidol60–702–6 h (PO)

      10–20 min (SC)
      13–35Multiple
      Levomepromazine (not USA)401–3 h (PO)

      30–90 min (SC)
      15–30Multiple
      P450 isoenzymes not fully characterised; some metabolites are active.
      Olanzapine605–8 h34
      Unaffected by hepatic or renal impairment.
      (52
      In the elderly.
      )
      CYP1A2, CYP2D6
      Prochlorperazine6

      14 (buccal)
      4 h (PO)

      4–8 h (buccal); shorter with multiple doses
      15–20Multiple
      Quetiapine1001.5 h7
      Clearance reduced by both renal and hepatic impairment.
      (10–14
      In the elderly.
      )

      (12
      Of active metabolite.
      )
      CYP3A4
      Risperidone991–2 h24
      For risperidone + active 9-hydroxy metabolite.
      Clearance reduced by renal impairment: see Product Monograph.
      CYP2D6
      Activity of 9-hydroxyrisperidone, the predominant CYP2D6 metabolite, is comparable to risperidone; thus overall clinical effect is not altered by CYP2D6 polymorphisms or inhibitors.
      a P450 isoenzymes not fully characterised; some metabolites are active.
      b Unaffected by hepatic or renal impairment.
      c In the elderly.
      d Clearance reduced by both renal and hepatic impairment.
      e Of active metabolite.
      f For risperidone + active 9-hydroxy metabolite.
      g Clearance reduced by renal impairment: see Product Monograph.
      h Activity of 9-hydroxyrisperidone, the predominant CYP2D6 metabolite, is comparable to risperidone; thus overall clinical effect is not altered by CYP2D6 polymorphisms or inhibitors.

      Cautions

      For full list, see manufacturer’s Package Insert.

      Stroke Risk

      Meta-analysis of RCTs in the elderly with dementia has shown that the risk of stroke with olanzapine and risperidone is 2–3 times higher compared with placebo,
      • Wooltorton E.
      Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials.
      • Wooltorton E.
      Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials.
      • Bullock R.
      Treatment of behavioural and psychiatric symptoms in dementia: implications of recent safety warnings.
      • Schneider L.S.
      • Dagerman K.S.
      • Insel P.
      Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.
      with a doubling of all-cause mortality with olanzapine.
      • Wooltorton E.
      Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials.
      The mechanism of this association is not known, but it is regarded as a class effect. Subsequent findings indicate an increased risk in all elderly patients for both typicals and atypicals,
      • Haddad P.M.
      • Sharma S.G.
      Adverse effects of atypical antipsychotics: differential risk and clinical implications.
      • Wang P.S.
      • Schneeweiss S.
      • Avorn J.
      • et al.
      Risk of death in elderly users of conventional vs. atypical antipsychotic medications.
      • Gill S.S.
      • Bronskill S.E.
      • Normand S.L.
      • et al.
      Antipsychotic drug use and mortality in older adults with dementia.
      • Ray W.A.
      • Chung C.P.
      • Murray K.T.
      • Hall K.
      • Stein C.M.
      Atypical antipsychotic drugs and the risk of sudden cardiac death.
      greatest in those with dementia,
      • Douglas I.J.
      • Smeeth L.
      Exposure to antipsychotics and risk of stroke: self controlled case series study.
      within the first month of starting treatment, and with higher doses. The relative risk with individual drugs has not yet been determined.

      Epilepsy

      Similar to many other psychotropic medications, antipsychotics cause a dose-dependent reduction in seizure threshold. The risk for individual agents approximates to the degree of sedation: chlorpromazine and clozapine carry a higher risk and haloperidol a lower risk. To minimize the risk, use the lowest risk antipsychotic (e.g., haloperidol) at the lowest effective dose. In palliative care, depot formulations are best avoided because they cannot be withdrawn quickly if problems occur.

      Parkinsonism and Parkinson’s Disease

      All antipsychotics, through D2 antagonism, can cause parkinsonism or worsen existing parkinsonism of any etiology. The risk is lower with clozapine and quetiapine. In patients with parkinsonism, alternatives to antipsychotics should be used where possible, e.g., for agitation, consider trazodone or a benzodiazepine, for nausea and vomiting consider:
      • domperidone (available as a suppository)
      • ondansetron
      • scopolamine (hyoscine) hydrobromide, but may cause delirium.
      Nonetheless, at the end of life, despite being D2 antagonists, it may be necessary to prescribe small doses of chlorpromazine, olanzapine or quetiapine if all else fails.
      Where delirium or psychotic symptoms occur in the context of Parkinson’s disease or Lewy body dementia:
      • look for potentially reversible causes of delirium, e.g., sepsis
      • consider a trial reduction of antiparkinsonian medication:
        • reduce dopamine receptor agonists and antimuscarinic agents initially
        • dopamine precursors, e.g., levodopa, are less likely to cause psychosis.
          • Weintraub D.
          • Hurtig H.I.
          Presentation and management of psychosis in Parkinson’s disease and dementia with Lewy bodies.
      If the above measures are unhelpful, commence quetiapine 12.5–25 mg/24 h; if not tolerated, seek specialist advice. Options include switching to clozapine.
      • Weintraub D.
      • Hurtig H.I.
      Presentation and management of psychosis in Parkinson’s disease and dementia with Lewy bodies.

      Drug Interactions

      For full list, see manufacturer’s Package Insert.
      Several pharmacodynamic interactions (additive sedation, hypotension and QT prolongation; reduced effect of antiparkinsonian medication) can be predicted from the receptor profile of antipsychotics.
      Potentially serious interactions may result from induction or inhibition of hepatic metabolism. CYP3A4 inhibitors (e.g., aprepitant, cimetidine, macrolide antibiotics, ketoconazole) can significantly increase plasma levels of aripiprazole, pimozide and quetiapine. Carbamazepine and protease inhibitors exhibit varied interactions.
      Antipsychotics are one of several classes of drugs that can prolong the QT interval, and at least theoretically increase the risk of cardiac tachyarrthymias, including potentially fatal torsade de pointes. Generally, concurrent prescribing of two drugs which can significantly prolong the QT interval should be avoided (see www.azcert.org).

      Undesirable Effects

      For full list, see manufacturer’s Package Insert.
      A summary is given in Box A.
      Undesirable Effects of Antipsychotics

        Extrapyramidal syndromes

      • Parkinsonism, akathisia, dystonia, tardive dyskinesia.
        • Twycross R.
        • Wilcock A.
        Drug induced movement disorders.

        Metabolic effects
        • Haddad P.M.
        • Sharma S.G.
        Adverse effects of atypical antipsychotics: differential risk and clinical implications.
        • Yood M.U.
        • DeLorenze G.
        • Quesenberry Jr., C.P.
        • et al.
        The incidence of diabetes in atypical antipsychotic users differs according to agent–results from a multisite epidemiologic study.

      • More common with typicals and risperidone
      • Hyperprolactinemia resulting in amenorrhea, galactorrhea, gynecomastia, sexual dysfunction, osteoporosis.
      • More common with atypicals, particularly olanzapine and clozapine
      • Weight gain.
      • Dyslipidemia, possibly associated with weight gain.
      • Type 2 diabetes mellitus, both new onset and exacerbation of pre-existing disease; risk independent of weight gain.

        Cardiovascular effects

      • QT prolongation: dose-related, affected by presence of other risk factors, highest risk with thioridazine (withdrawn) and ziprasidone.
        • Haddad P.M.
        • Sharma S.G.
        Adverse effects of atypical antipsychotics: differential risk and clinical implications.
        • Twycross R.
        • Wilcock A.
        Prolongation of the QT interval in palliative care.
      • Venous thromboembolism; risk possibly highest with atypicals.
        • Liperoti R.
        • Pedone C.
        • Lapane K.L.
        • et al.
        Venous thromboembolism among elderly patients treated with atypical and conventional antipsychotic agents.
      • Stroke and increased risk of death in elderly patients (see Cautions).
      • Postural hypotension (α-adrenergic antagonism), particularly phenothiazines and clozapine; also seen with quetiapine and risperidone.

        Miscellaneous
        • Haddad P.M.
        • Sharma S.G.
        Adverse effects of atypical antipsychotics: differential risk and clinical implications.

      • Reduced seizure threshold (see Cautions).
      • Antimuscarinic effects; more with phenothiazines and clozapine.
      • Neuroleptic (antipsychotic) malignant syndrome (see below).
      • Agranulocytosis is seen in about 1% of patients taking clozapine, generally after 3–6 months.

      Neuroleptic (Antipsychotic) Malignant Syndrome

      Neuroleptic (antipsychotic) malignant syndrome (NMS) is a potentially life-threatening reaction that occurs in <1% of those prescribed an antipsychotic (Box B).
      • Caroff S.
      • Mann S.
      Neuroleptic malignant syndrome.
      • Adnet P.
      • Lestavel P.
      • Krivosic-Horber R.
      Neuroleptic malignant syndrome.
      This idiosyncratic syndrome is associated with all antipsychotics.
      • Isbister G.K.
      • Dawson A.H.
      • Whyte I.M.
      Comment: neuroleptic malignant syndrome associated with risperidone and fluvoxamine.
      Clinical Features of Neuroleptic (Antipsychotic) Malignant Syndrome

        Essential

      • Severe muscle rigidity
      • Pyrexia ± sweating

        Additional

      • Muteness γ stupor
      • Tachycardia and elevated/labile blood pressure
      • Leukocytosis
      • Raised plasma creatine phosphokinase ± other evidence of muscle injury, e.g., myoglobinuria
      Most cases of NMS occur within two weeks of starting treatment or a dose increase. It is a hypodopaminergic state; bradykinesia progresses to immobilization, akinesia and stupor, accompanied by lead-pipe rigidity, fever, and autonomic instability.
      Symptoms indistinguishable from NMS have been reported in patients with Parkinson’s disease when long-term treatment with levodopa and bromocriptine has been abruptly discontinued.
      • Keyser D.L.
      • Rodnitzky R.L.
      Neuroleptic malignant syndrome in Parkinson’s disease after withdrawal or alteration of dopaminergic therapy.
      • Mann S.C.
      • Caroff S.N.
      Pathogenesis of neuroleptic malignant syndrome.
      • Ong K.C.
      • Chew E.L.
      • Ong Y.Y.
      Neuroleptic malignant syndrome without neuroleptics.
      This has led to the suggestion that the syndrome would be better called acute dopamine depletion syndrome.
      • Keyser D.L.
      • Rodnitzky R.L.
      Neuroleptic malignant syndrome in Parkinson’s disease after withdrawal or alteration of dopaminergic therapy.
      Death occurs in up to 20% of cases, mostly as a result of respiratory failure. The use of a dopamine agonist, e.g., bromocriptine, halves the mortality.
      • Sakkas P.
      • Davis J.M.
      • Hua J.
      Pharmacotherapy of neuroleptic malignant syndrome.
      Subsequent prescription of an antipsychotic carries a 30–50% risk of recurrence.
      • Wells A.J.
      • Sommi R.W.
      • Crismon M.L.
      Neuroleptic rechallenges after neuroleptic malignant syndrome: case report and literature review.
      NMS is self-limiting if the causal antipsychotic drug is discontinued (and an alternative antipsychotic not prescribed). Generally it resolves in 1–2 weeks unless caused by a depot antipsychotic, when it takes 4–6 weeks. Antipsychotics are not removed by hemodialysis. Specific measures include:
      • discontinuation of the causal drug
      • prescription of a muscle relaxant, e.g., a benzodiazepine
      • in severe cases, prescription of bromocriptine.
        • Sakkas P.
        • Davis J.M.
        • Hua J.
        Pharmacotherapy of neuroleptic malignant syndrome.
      General supportive measures may need to extend to artificial hydration and nutrition. Complications such as hypoxia, acidosis and renal failure require appropriate acute management.

      Use of Antipsychotics in Palliative Care

      For greater detail about doses, see the individual drug monographs in the Hospice and Palliative Care Formulary USA
      • Twycross R.
      • Wilcock A.
      Hospice and palliative care formulary USA.
      or the Palliative Care Formulary (Canadian edition),
      • Twycross R.
      • Wilcock A.
      • Dean M.
      • Kennedy B.
      Canadian palliative care formulary.
      or visit www.palliativedrugs.com.

      Nausea and vomiting

      The D2 antagonism of all antipsychotics is likely to provide anti-emetic activity in the area postrema (chemoreceptor trigger zone). Where specific action at this site is required (e.g., most chemical causes of nausea), a selective dopaminergic agent such as haloperidol is used,
      • Büttner M.
      • Walder B.
      • von Elm E.
      • Tramèr M.R.
      Is low-dose haloperidol a useful antiemetic? A meta-analysis of published and unpublished randomized trials.
      although studies in palliative care patients are lacking.
      • Perkins P.
      • Dorman S.
      Haloperidol for the treatment of nausea and vomiting in palliative care patients.
      However, most antipsychotics have moderate or high affinity at several receptors, some of which are involved in the transduction of emetic signals.
      • Twycross R.
      • Wilcock A.
      Antiemetics.
      Thus, most antipsychotics are, to a variable extent, broad-spectrum anti-emetics. Levomepromazine (not available in the USA) and olanzapine are the most attractive choices (and haloperidol is the least) in this respect.
      • Passik S.D.
      • Navari R.M.
      • Jung S.H.
      • et al.
      A phase I trial of olanzapine (Zyprexa) for the prevention of delayed emesis in cancer patients: a Hoosier Oncology Group study.
      • Navari R.M.
      • Einhorn L.H.
      • Passik S.D.
      • et al.
      A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study.

      Delirium

      Treatment of underlying causes, non-drug management (e.g., orientation strategies, correction of sensory deprivation) and prevention of complications are central to delirium management.
      When medication is required, antipsychotics are often used, e.g., haloperidol, although evidence is limited and comparative studies with other psychotropics are lacking.
      • Fong T.G.
      • Tulebaev S.R.
      • Inouye S.K.
      Delirium in elderly adults: diagnosis, prevention and treatment.
      • Caraceni A.
      • Simonetti F.
      Palliating delirium in patients with cancer.
      • Attard A.
      • Ranjith G.
      • Taylor D.
      Delirium and its treatment.
      When antipsychotics alone are insufficient, or when sedation also is required, e.g., for the initial management of a hyperactive, frightened patient, benzodiazepines or trazodone can be added.
      Benzodiazepines can paradoxically worsen agitation, but are preferred for delirium related to alcohol withdrawal, neuroleptic malignant syndrome or Parkinson’s disease. The use of cholinergics has been reported, but rivastigmine increased mortality in an RCT.
      • van Eijk M.M.
      • Roes K.C.
      • Honing M.L.
      • et al.
      Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial.
      Hallucinations in delirium respond to antipsychotics in hours–days, whereas seemingly identical phenomena in a psychosis may not resolve for 1–2 weeks.

      Agitation and challenging behaviors in dementia

      Patients with dementia may become agitated for many reasons, including an appropriate response to a distressing situation. Possible precipitants should be treated or modified:
      • intercurrent infections
      • pain and/or other distressing symptoms
      • environmental factors.
      When no reversible cause is found and agitation is mild, assurance that such behaviors are often self-limiting may suffice. Training in non-drug management of behavioral disturbances reduces the need for psychotropic medication.
      • Fossey J.
      • Ballard C.
      • Juszczak E.
      • et al.
      (2006) Effect of enhanced psychosocial care on antipsychotic use in nursing home residents with severe dementia: cluster randomised trial.
      The first-line use of antipsychotics for behavioral disturbance in dementia is inappropriate and actively discouraged.
      • Mowat D.
      • Fowlie D.
      • MacEwan T.
      CSM warning on atypical psychotics and stroke may be detrimental for dementia.

      Health Canada. Increased mortality associated with the use of atypical antipsychotic drugs in elderly patients with dementia. Notice to healthcare professionals. 2005. Available from www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2005/atyp-antipsycho_hpc-cps-eng.php.

      US Food and Drug Administration. Alert. Information on antipsychotics (6/16/2008). 2008. Available from www.fda.gov/Drugs,

      In addition to safety concerns (increased risk of stroke and overall mortality, see above), evidence of benefit compared with non-drug measures is limited. A recent large RCT for agitation or psychosis in patients with dementia found both atypicals and typicals to be no better than placebo in all but a few secondary outcomes.
      • Schneider L.S.
      • Tariot P.N.
      • Dagerman K.S.
      • et al.
      Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease.
      Taken together with other studies, the efficacy of antipsychotics in dementia is at best modest, and should be used only where other measures have failed.
      • Jeste D.V.
      • Blazer D.
      • Casey D.
      • et al.
      ACNP White Paper: Update on use of antipsychotic drugs in elderly persons with dementia.
      • Ballard C.G.
      • Gauthier S.
      • Cummings J.L.
      • et al.
      Management of agitation and aggression associated with Alzheimer disease.
      The use of alternative drugs, i.e., antidepressants, benzodiazepines, antiepileptics and cholinesterase inhibitors, has been proposed. However, evidence is generally more limited than for antipsychotics, and insufficient to allow clear evidence-based recommendations of one class over another.
      • Jeste D.V.
      • Blazer D.
      • Casey D.
      • et al.
      ACNP White Paper: Update on use of antipsychotic drugs in elderly persons with dementia.
      • Sink K.M.
      • Holden K.F.
      • Yaffe K.
      Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence.
      Further, larger studies have not replicated the earlier benefit reported for trazodone.
      • Jeste D.V.
      • Blazer D.
      • Casey D.
      • et al.
      ACNP White Paper: Update on use of antipsychotic drugs in elderly persons with dementia.
      Even so, the serious consequences of not treating severe agitation or psychosis in dementia also are recognized.
      • Jeste D.V.
      • Blazer D.
      • Casey D.
      • et al.
      ACNP White Paper: Update on use of antipsychotic drugs in elderly persons with dementia.
      Where drug treatment is required, clinicians should be guided by the individual patient’s symptoms and co-morbidities, and the clinicians’ familiarity with the agents available. Options include:
      • haloperidol
      • atypicals, e.g., olanzapine, quetiapine, risperidone
      • cholinesterase inhibitors (benefit is marginal, but may be better tolerated).
        • Sink K.M.
        • Holden K.F.
        • Yaffe K.
        Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence.
      Whichever drug is selected, use the lowest effective dose for the shortest possible time; attempt dose reduction every 2–3 months; many patients do not deteriorate when medication is withdrawn.
      • Ballard C.G.
      • Gauthier S.
      • Cummings J.L.
      • et al.
      Management of agitation and aggression associated with Alzheimer disease.
      • Sink K.M.
      • Holden K.F.
      • Yaffe K.
      Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence.
      • Lee P.E.
      • Gill S.S.
      • Freedman M.
      • et al.
      Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review.

      Intractable hiccup

      Chlorpromazine or haloperidol are used when more specific treatment, e.g., simethicone (an antifoaming agent) ± metoclopramide for gastric distension, or baclofen are ineffective.
      • Twycross R.
      • Wilcock A.
      • Toller C.S.
      Symptom management in advanced cancer, 4th ed.

      Refractory depression

      Certain antipsychotics have been used as adjuncts for depression refractory to conventional antidepressants, particularly when switching antidepressants has been unsuccessful. Generally, either quetiapine or olanzapine is added to an SSRI.
      • Shelton R.C.
      • Osuntokun O.
      • Heinloth A.N.
      • Corya S.A.
      Therapeutic options for treatment-resistant depression.

      National Institute for Health and Clinical Excellence (NICE). Clinical guideline 90. Depression. London: NICE, 2009. Available from www.nice.org.uk.

      • Anderson I.M.
      • Ferrier I.N.
      • Baldwin R.C.
      • et al.
      Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.

      Pain

      Dopamine is implicated in pain processing
      • Wood P.B.
      Mesolimbic dopaminergic mechanisms and pain control.
      and, in the past, antipsychotics were sometimes used as part of an analgesic cocktail. However, RCTs yield conflicting results.
      • Seidel S.
      • Aigner M.
      • Ossege M.
      • et al.
      Antipsychotics for acute and chronic pain in adults.
      Although no longer used as analgesics themselves, antipsychotics are helpful for treating the undesirable effects of analgesics, particularly nausea and delirium.
      • Coyle N.
      • Breitbart W.
      • Weaver S.
      • Portenoy R.
      Delirium as a contributing factor to ‘crescendo’ pain: three case reports.

      Switching Antipsychotics

      Equivalent doses of typicals have been estimated, predominantly from surveys of psychiatric practice, and provide a starting point if switching from one to another (Table 4).
      • Foster P.
      Neuroleptic equivalence.
      However, the dose of atypicals is less variable and thus their starting dose is unaffected by the dose of previous antipsychotics.
      Table 4Equivalent Doses of Typical Antipsychotics
      • Foster P.
      Neuroleptic equivalence.
      DrugDose (mg)
      Chlorpromazine100
      Promazine100
      Perphenazine8
      Trifluoperazine5
      Haloperidol3

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